The current name is PRIMARY CNS LYMPHOMAS (PCNSL). Few other tumors have had so many different names, which include malignant lymphoma, non Hodgkin’s lymphoma, microgliomatosis, microglioma, reticuluim cell sarcoma, microgrliomatosis, perivascular sarcoma, reticulendothelial sarcoma, malignant reticulosis, malignant, reticulo-endotheliosis, histocytic lymphoma, immunoblastic sarcoma and granulomatous encephalitism. Much of the older American literature has referred to these tumors as reticulum cell sarcomas because of the similarity with tumors of lymph node origin. In Europe the term microglioma was preferred because of the microlglial like silver staining properties of cells within these tumors. It now appears however that these cells are reactive and not an intrinsic component of the tumor.

The above list of names reflects the past uncertainty regarding  the cell of origin of this tumor. These tumors were, now, found to be almost exclusively B cell lymphomas of the non Hodgkin’s type, as confirmed by immunocytochemical and latterly molecular genetic studies.

Epidemiology:

PCNSL represents rare form of non-Hodgkin's lymphoma, and account for <1% of all primary brain tumors and 1% of non-Hodgkin’s lymphomas. However the incidence is increasing both in immunosuppressed and in non immunosupporessed patients and this important findings is unexplained.

Although diagnosed predominantly among immunocompetent, those immunosuppressed patients are at particular risk of developing PCNSL and they can be divided into four groups:

Patients with AIDS of whom approximately 3% will develop PCNSL and in whom PCNSL is the most common cause of a non-infectious intracranial mass lesion.

Reports suggest that there is annual incidence of primary cerebral lymphoma between 0.22%-1.6% in renal and cardiac transplant recepients. This represents an increased risk to that of the general population by 350 fold.

Patients with congenital immunodeficiency states where the risk of developing PCNSL is approximately 4%.

Other rare associations of the tumor with drug or disease induced immunosuppresion include sarcoidosis, systemic lupus erthematous, Sjogren’s syndrome, vasculitis, rheumatoid arthritis, idiopathic thrombocytopenic purpura and progressive multifocal leucoencephalopathy.

The associated conditions without evidence of immunosuppression include tuberculosis, multiple sclerosis and other malignancies.

Patient of any age can be affected, although most non-immunosuppressed patients present in their 5^th-7^th decades with a mean age of 57. Most series of non-immunosuppressed patients show an increased incidence in men with an approximate male to female ratio of 2:1. Patients with AIDS presenting with the disease are usually male and age 30-40.

Pathology:

Although the tumor's origin principally as a B cell lymphoma has been determined, how these neoplastic cells come to proliferate within the central nervous system is not understood and why they are so frequently multifocal at presentation is primary CNS tumor that may completely disappear with steroids adds to the interesting nature of the tumor. 

The CNS has neither lymphatic circulation nor physiological accumulations of lymphoid tissue: a fact which has led to different theories regarding the origin of the neoplastic lymphoid cells in the CNS. 

There are two possible theories of origin.

Firstly, a non neoplastic reactive population of lymphocytes is attracted into the CNS by an inflammatory or infectious event and then transformed locally into a neoplastic clone. The transforming factor has been proposed to be a virus. This clone may then express a binding molecule specific to the CNS or CNS vascular endothelium, allowing the cells to spread via the bloodstream but only adhering to the CNS.  One piece of supporting evidence for this theory is the knowledge of chronic viral infections of the CNS which evade immune surveillance.

The second theory suggests that a clone of B lymphocytes possessing a CNS specific binding site proliferate outside the CNS and are transformed into neoplastic cells which circulate but only bind to the CNS.  The site of origin remains obscure while the clone proliferates within the CNS.  This latter theory incorporates a proposed vascular spread with a CNS binding site, which explains the high incidence of multifocality at presentation, and also the peculiar attraction for the CNS. However it does not account for the increased frequency of occurrence adjacent to the ventricle or within the frontal lobes.  A blood borne tumor, even if possessing a specific CNS marker, should occur at the more common sites for metastatic tumor i.e. the parietal lobe while an intrinsic tumor would be expected to occur most often in the largest area of brain, i.e. the frontal lobe.

It is likely that while the etiology of PCNSL in the non-immunosuppressed remains obscure, in immunosuppressed individuals with reduced immune surveillance (under T cell control) the Epstein Barr virus (EBV) may be directly implicated.  The EBV genome has been identified in cells from PCNSL in both immunosuppressed and non-immunosuppressed patients.  However in one report, using an in-situ hybridization technique with a biotinylated DNA probe to the internal repeat regions of the EBV genome, evidence of EBV was found in all 5 cases of immunosuppressed PCNSL but in only 2 of 43 non-immunosuppressed patients (Geddes, 1992).  The association of EBV genome to PCNSL in immunosuppressed patients could represent secondary infection; however the EBV genome was identified in neoplastic cells rather than adjacent reactive cells.

In vitro studies of peripheral lymphoma cell lines suggest that the expression of activated c-myc (a proto-oncogene) in combination with infection by EBV causes tumorigenesis, however, studies of PCNSL have usually failed to show these c-myc rearrangements.

Further use of molecular biological techniques may identify specific CNS markers, other viral DNA or consistent patterns of genetic abnormalities associated with these tumors and thereby lead to a better understanding of their origin.

Primary CNS lymphoma usually manifests in the brain (30-50%), leptomeninges (10-25%), eye (10-20%), or spinal cord.

PCNSLs may occur in any location in the brain; but they are most commonly found in the cerebral hemispheres. 

The frontal lobe is the most common site and the occipital lobe the least common. 

They usually lie deeply within the basal ganglia or adjacent to the ventricle. 

Spread may involve the corpus callosum, producing the so called ‘butterfly tumor’ or be subependymal or meningeal. 

Lesions below the tentorium occur and when present are most often situated in the cerebellum. 

Multiple lesions are found at presentation in 30-50%,  but are more common in the immunosuppressed at 50-80%. Other primary site include the eyes, cranial or spinal nerves and although spinal meningeal disease occurs it is much more common with recurrence and neuroaxis dissemination.

Macroscopically the lesions can vary greatly in appearance, some being well defined yellow-white lesions quite distinct from normal white matter, other may be grey or brown.  Some may show diffuse discoloration and swelling or appear grossly normal. Cyst formation is rare but necrosis and hemorrhage may be present.  The tumors may act as space occupying lesions with significant edema and mass effect or they may be ill defined and diffuse. Typically they replace rather than displace normal brain with resultant little mass effect.

Microscopically PCNSL are richly cellular with large round or oval cells with a lymphoid appearance. They have round, oval or kidney shaped nuclei.  Necrosis is common; mitotic figures and varying degrees of pleomorphism may also be present.  One characteristic feature of these tumors is their perivascular orientation with infiltration and distension of the perivascular spaces.  This is demonstrated by reticulin stains which show concentric rings around blood vessels representing reduplication of reticulin. Endoepthelial proliferation is not typical but spread via perivascular spaces in adjacent brain is, resulting in a diffuse infiltration with neoplastic cells being found distant to the macroscopic borders of the tumor. 

Leptomeningeal spread is also characteristic. They may resemble bacterial meningitis with semi liquid tissue lying with the meninges or producing thickening of the cranial or spinal nerves.  This tissue may fill the sulci and basal cisterns and obscure the cortical surface.  In the spinal cord the cauda equina may be matted together. The cells do not form follicles or nodules. Immunological and molecular genetic studies have shown that these are B cell lymphomas. T cell lymphomas occur very rarely in only 1-2% although T cells may be present when they are likely to represent an inflammatory response.

Systemic spread of PCNSL is found at necropsy in 7-34%; however in the majority of cases this is clinically silent and usually occurs in the presence of recurrent CNS disease. 

Secondary involvement of the CNS by systemic lymphoma will develop in 2-10% of cases of non Hogkin’s lymphoma. This usually present as extradural compression in the spinal canal but other sites, including intracranial extradural, meningeal and intraparenchymal deposits, do occur, although rarely.  Systemic Hodgkin’s disease seldom involves the CNS and primary CNS Hodgkin’s lymphoma is extremely rare.

Clinical presentation:

The signs and symptoms produced by PCNSL reflect their location and pathological behavior.

The presenting history is often only a few months and most patients present with a space occupying lesion or lesions producing local deficits.  As a frontal location is commonest, accordingly motor dysfunction, personality or other neuro psychological deficits appear frequently in 20-30%.  Subtle changes of personality, depression or memory loss may also reflect diffuse involvement of white matter tracts, particularly in association with periventricular and corpus callosum lesion.

Patients with mass lesions and raised intracranial pressure may present with headache but this may also suggest meningeal involvement and other signs of meningism or cranial and spinal nerve dysfunction should be looked for. 

Seizures occur in 5-25% of patients,  The pattern of clinical presentation may mimic other pathology such as cerebrovascular accident or encephalitis. Infratentorial lesions cause ataxia, cranial nerve lesions or other disturbances of brain stem function. 

Spinal deposits occur frequently with recurrence but primary intramedullary non Hodgkin’s lymphoma is very rare.

There is a significant incidence of visual disturbance and this may be either lymphoma affecting the uvea, choroid or retina or pathology affecting the intracranial visual pathways.

Slit lamp examination of patients with suspected intracranial disease should be carried out as it may show occult disease.

Radiology:

MRI shows the tumors to be iso or hyperintense to grey matter on T2 weighted images with homogeneous enhancement after contrast.  Multiplicity of lesions is found in 40% of MRIs performed but MRI has not been shown to significatly better than CT in making the diagnosis.

In one study using CT 29% of patients had multiple lesions and in this series the prognosis of this group was not significantly worse than in those who had single lesions on CT.

Positron emission tomography (PET) with HC-methyl-L-methionine has been shown to be useful in following the response to therapy as these lesions may temporarily disappear on CT after steroids or other therapy.

This rapid disappearance is unique among cerebral tumors but multiple sclerosis and sarcoidosis are other possibilities.

The differential diagnosis of a mass lesion includes metastases high grade astrocytoma, secondary lymphoma, meningioma, abcess and toxoplasmosis.  Radiological features such as a periventricular site or mass with ependymal/meningeal enhancement are highly suggestive and may increase the chance of a positve diagnosis being obtained from the CSF.

Diagnosis:

Although the diagnosis may be suspected radiologically, histological verification is required. 

In 10% of patients, particularly those with subependymal and periventricular involvement, lumbar puncture and CSF cytology may provide the diagnosis.  Immunostaining with B and T cell markers is very useful in the identification and classification of PCNSL and may demostrate monoclonal populations even if the cells appear cytologically benign. 

The CSF biochemistry commonly shows a raised protein level with normal glucose content, and white blood cell pleocytosis.

If CSF cannot be obtained safely or cytology is inconclusive, needle biopsy should be performed preferably using CT guided stereotaxy.  If craniotomy is performed and per-operative smear indicates lymphoma then aggressive surgical excision is not justified.  The extent of surgical excision has not been shown to have an effect on quality or length of survival.

The surgeon should also bear in mind that these tumors usually show a very good early response to adjuvant therapy even in patients with a significant tumor bulk.

Although staging is carried out in many centers and as part of some trial protocols, systemic non Hodgkin’s lymphoma is found in <5% patients presenting with cerebral lymphoma. There are no reported cases of occult systemic lymphoma presenting as a CNS lymphoma. Thus CT scanning of thorax and abdomen and bone marrow examination are unnecessary unless clinically indicated.  However, if it can be performed safely, CSF should be obtained as positive cytology suggests ependymal or meningeal involvement and the patient should then be considered for intrathecal methotrexate therapy.

Slit lamp examination of the eye and serology for syphilis and HIV antigen should also be carried out.

Treatment:

The neurosurgeon will see these tumors with increasing frequency over time but the role of surgery in management is principally to suspect the diagnosis and then confirm it by biopsy.

After histological confirmation the oncologist/radiotherapist will contribute most to overall therapy. 

Steroids have an immediate and dramatic impact on symptoms.  There are a number of reports of tumors disappearing on cT after steroids. This is a direct cytotoxic effect but, while in some remission may be sustained for months, most relapse within weeks.  Disappearance of the tumor after initiation of steroid therapy will make sterotactic biopsy impossible although the tumor may still be detected by PET scanning. Some recommend withholding steroid therapy until after biopsy unless the patient is at risk. The reappearance of the tumor either with or without cessation of steroids will allow biopsy if CSF is negative.

Radiotherapy: Traditional therapy for primary cerebral lymphoma has been post operative radiotherapy. These tumors are generally radiotherapy responsive, although less so than when they arise outside the CNS.  However this response is not sustained and 80-95% of cases recur, usually between 10-12 months after therapy. The prognosis with radiotherapy alone after biopsy is a median survival of 10-18 months although much worse results have been reported. Radiotherapy is usually given to the brain down to C2 and if there is ocular involvement the orbits are included.  A total dose of 4000 to 5000 cGy is recommended to the whole brain but whether there is any additional benefit from a boost to the tumor itself is unclear although recommended.

Most PCNSL recur within the fields of radiation treatment.  PCNSL exhibit a high rate of multicentricity and diffusely infiltrate the brain parenchyma, deposits in so called retinal and subarchnoid sanctuaries also occur and these may not be demonstrated on enhanced CT or MRI. In light of these observations and the poor prognosis despite radiotherapy, chemotherapy is being increasingly used.

Chemotherapy:   Most modern chemotherapeutic regimes, of which there are several, include high dose MTX which penetrates the CNS relatively well but may cause leukoencephlopathy when used following radiotherapy.

There are a number of different chemotherapy regimes in use for pre or post irradiation treatment and a combination of pre and post irradiation chemotherapy has also been employed. Results with chemotherapy have improved median survival from 14 months to 18 to 44 months.  Deferring the use of radiotherapy after chemotherapy until recurrence has also been advocated by some. Treatment of patients with radiological or cytological evidence of meningeal disease is recommended with intrathercal MTX either via a lumbar puncture or a ventricular catheter connected to an Ommaya reservoir.

DeAngelis has employed a combined modality therapy with systemic MTX and intrathecal MTX via an Ommaya reservoir into the ventricle pre-radiotherapy, followed by cytarabine systemically post radiotherapy.

Neuwelt  have been using an intensive regime including blood brain barrier modulation with intracarotid or vertebral mannitol prior to intra-arterial chemotherapy.  Both groups have published improved survival data with a median survival around 43 months.

Whether or not these intensive treatment regimes will prove generally applicable or effective and what the patient selection criteria should be for different therapies remains to be clarified. 

Nevertheless there is accumulating evidence to suggest that patients should be offered chemotherapy following biopsy and prior to radiotherapy.

Patients with AIDs presenting with PCNSL are usually treated with steroids and radiotherapy as their already immunosuppressed condition often rules out chemotherapy.  The mean survival time for this group is 3-5.5 months.

Prognosis:

Approximately 80-95% if tumors recur locally within the radiation fields. 93% of recurrences are confined to the CNS with neuroaxis dissemination in 60%. Systemic spread of PCNSL is found at necropsy in 7-34%; however in the majority of cases this is clinically silent and rarely occurs in the absence of recurrent CNS disease. The 5 year survival is approximately 2-5% and most patients die from local disease within 2 years of diagnosis with a median survival of 10-18 months after radiotherapy. 

With chemotherapy with or without radiotherapy median survival is improved to 17-44 months.

Positive prognositc indicators include a solitary intracranial lesion, favorable histology and the administration of radiotherapy or chemotherapy. 

Adverse factors include periventricular/meningeal lesions and immunosuppression. It has been suggested that an elevated CSF protein >0.6g per litre is the strongest negative prognostic indicator while the other negative factors included performance status and age over 60.